Our investigations concern the resistance of Plasmodium falciparum to several common antimalarial drugs: the dihydrofolate reductase inhibitor pyrimethamine, and the quinoline ring derivatives chloroquine, quinidine and mefloquine. We are crosses of cloned parasite lines to identify the genes that affect susceptibility to these drugs. Point mutations in the gene encoding dihydrofolate reductase-thymidylate synthase have been found to confer pyrimethamine resistance in malaria. Chloroquine resistance has been found to be governed by a single gene in linkage studies. RFLP analysis is being to pinpoint the location of this gene. A similar approach is being used to identify affecting erythrocyte- stage proliferation. In a cross between two clones the faster proliferation rate of one parent predominated in progeny recovered after cross fertilization and infection of chimpanzees. Linkage group analysis suggests an association between a genetic locus near a telomere of chromosome 13 and the rapid proliferation rate. Investigations are now planned to map the genes involved and examine for relationship to sialic acid and erythrocyte-binding proteins thought to modulate erythrocyte invasion by P. falciparum.